Polymeric hydrogel matrices have been described as biomaterials useful for the treatment of a variety of medical conditions. (See, for example, U.S. Pat. Nos. 5,529,914, 5,854,382, 6,007,833, 6,051,248, 6,153,211, 6,316,522, 6,818,018, and 7,070,809.) Depending on the polymeric material used, these matrices may be biostable, or biodegradable following a period of implantation. The polymeric material used to form these matrices is desirably biocompatible, meaning that it does not have an adverse biological effect on the organism in which the hydrogels are placed or formed. Accordingly, it is generally desirable to avoid the use of biodegradable materials that degrade into products that cause unwanted side effects in the body by virtue of their presence or concentration in vivo. These unwanted side effects can include immune reactions, toxic buildup of the degradation products in the liver, or the initiation or provocation of other adverse effects on cells or tissue in the body.
The ability of the hydrogel matrices to provide a positive effect for the treatment of a subject may occur by the structural and chemical properties of the hydrogel matrices mimicking the natural tissue and facilitating tissue healing. Hydrogel matrices may also exert a protective affect to tissues, thereby preventing tissue or cellular damage (for example in the case of an inflammatory response).
In some cases, hydrogel matrices may be associated with a drug that is designed to provide a therapeutic effect to tissue at the site the hydrogel is localized or formed. For example, it has been proposed to use a drug that is released from the matrix by diffusion, or released by the degradation of the hydrogel matrix, for treatment of a target tissue.
Hydrogel matrices have been proposed for medical use in a variety of forms. In some cases, hydrogel matrices can be formed as tissue-healing articles on a wound site, designed to promote tissue regeneration and healing of the wound. When applied this way, these hydrogel matrices are amorphous and typically conform to the tissue on which the hydrogel matrix-forming composition is applied. These matrices can be formed in situ, such as by the application of the matrix-forming composition on the treatment site and the treatment of the composition to cause crosslinking of the hydrogel forming material.
In other cases, hydrogel matrices can be formed in association with an implantable medical device. In these cases, the matrices may have a more distinct form, such as a coating on the surface of a device, or a fill that conforms to a void in the device.
Many challenges remain for the formation and use of hydrogel matrices as in situ formed articles, or in association with implantable medical devices.
In the case of biodegradable matrices, one challenge relates to the preparation of matrices having suitable degradation properties in vivo. For example, some natural polymers, such as hyaluronic acid and alginic acid, are biodegradable in polymeric form, but can be crosslinked to form non-biodegradable hydrogel matrices. On the other hand, hydrogel matrices formed from polymeric materials with a significant amount of ester linkages will typically degrade by bulk erosion. The bulk erosion may cause the matrices to degrade too rapidly and/or without control. This may cause matrix fragmentation resulting in the undesirable loss of embolic matrix fragments into the circulatory system.
In addition, many hydrogel matrices lack desirable physical properties, such as sufficient durability for implantable procedures, or controlled swelling. For example, matrices that are highly hydrophilic can rapidly absorb water and cause plasticization of the polymer, resulting in a soft gel-like matrix. This characteristic is undesirable as the matrix can tear upon expansion and ruin its physical integrity.
Some hydrogels of the prior art rely on chemical agents to cure the polymeric materials. Many of these chemical agents are small compounds that can cause tissue damage, and are therefore undesirably used in the body.
In addition, hydrogel matrices that are designed for drug release are generally not well developed. Hydrogel matrices intended to release a therapeutic agent have been problematic because release is typically inadequately controlled. For example, in many cases, the majority of the agent is released from the matrix in a short burst, resulting in depletion of the agent from the hydrogel matrices. This burst is particularly undesirable when a therapeutic effect is required over an extended period of time. The short term burst is thought to be caused by the hydrophilicity of the polymeric materials driving water into the matrix, causing an increase in the osmotic pressure in the coating. As a result, the permeability of the matrix for the drug is significantly increased, resulting in the elution of the drug at a therapeutically ineffective rate.
In addition, certain polymeric materials, reagents, and/or methods of preparing hydrogels may be incompatible with or unsuitable for certain therapeutic agents. For example, in technologies using polymeric macromers, hydrogel formation is typically carried out using a free radical-generating system. Unfortunately, free radicals can be damaging to many macromolecules, such as nucleic acids, and even cells. Also, the use of polymers with an abundance of charged groups as hydrogel forming materials may attract oppositely charged therapeutic agents and alter their release from the gel. Alternatively, matrices formed from highly charged polymers and including cellular material may cause undesirable cellular responses in the cells.
Embodiments of the present invention address one or more of these problems associated with hydrogel technologies of the prior art.